Detail of "6323-97-3"

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Using surface plasmon resonance to directly measure slow binding of low-molecular mass inhibitors to a VanX chip

All Rights Reserved. Using surface plasmon resonance to directly measure slow binding of low-molecular mass inhibitors to a VanX chip. Chang, Yi-Pin; Tseng, Min-Jen; Chu, Yen-Ho (Department of Chemistry and Biochemistry and Institute of Molecular Biology, National Chung Cheng University, Taichung 621, Taiwan). Analytical Biochemistry, 359(1), 63-71 (English) 2006 Elsevier. 7622-22-2 and 6323-97-3 are also occured in this study. CODEN: ANBCA2. ISSN: 0003-2697. DOCUMENT TYPE: Journal CA Section: 7 (Enzymes) Section cross-reference(s): 1 VanX, a D,D-dipeptidase, is one of five gene products responsible for vancomycin resistance in pathogenic bacteria and is an attractive drug target in circumventing clin. drug resistance. Our previous combinatorial search of VanX substrates in a dipeptide library of D-X1-D-X2 (192 = 361) forms has led to the discovery of three new compds. (D-Ala-D-Phe, D-Ala-D-Tyr, and D-Ala-D-Trp) having higher kcat/Km values than those of its natural substrate, D-Ala-D-Ala. Based on structures of newly identified substrates, two representative transition state analogs of substrates, D-Ala(P,O)D-Phe (6a) and D-Ala(P,O)D-Ala (6b) dipeptide phosphonates, used as VanX inhibitor were rationally designed and chem. synthesized. In the synthesis, eight synthetic steps in total were employed for prepg. each VanX inhibitor, and their overall isolated yields were 21 and 11% for 6a and 6b, resp. Binding interactions of D-Ala(P,O)D-Phe (6a) and D-Ala(P,O)D-Ala (6b) with VanX were confirmed unambiguously and measured quant. by surface plasmon resonance. The result reveals that both dipeptide phosphonates are slow-binding inhibitors of VanX (for 6a, kon = 1.18 ′ 103 M-1 s-1, koff = 2.31 ′ 10-3 s-1, KD = 1.96 mM, c2 = 0.0737; for 6b, kon = 1.09 ′ 103 M-1 s-1, koff = 1.80 ′ 10-2 s-1, KD = 16.5 mM, c2 = 0.0599). This suggests that only a fraction of the conformers of the inhibitors in soln. adopts a conformation best suited for binding interaction with VanX and that the VanX-inhibitor complex may concomitantly undergo a conformational isomerization from an initial but fast weak-binding adduct to slowly convert to a tight-binding complex with a more stable bound geometry. Moreover, in comparison with 6b, an addnl. arom. interaction of 6a with the Phe79 residue in the active site of the enzyme, through an energetically favorable face-to-face offset stacked orientation, may account for its higher affinity than 6b to VanX. .